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68 CHIRAL SEPARATION OF THE INOTROPIC AND CHRONOTROPIC ACTIONS OF DIGOXIN
  1. J. C. Somberg,
  2. C. Lin,
  3. I. Cvetanovic,
  4. X. Ke,
  5. J. Molnar,
  6. V. Ranade
  1. Chicago, IL

Abstract

Background Digoxin (D) prolongs conduction at the AV node and augments cardiac contractility by inhibition of Na+,K+-ATPase. The digoxin molecule is chiral having asymmetries at the C3 and C17 carbon centers that could give rise to stereoscopic isomers. The actions of D on cardiac conduction and contractility could be mediated through the different isoforms of Na+,K+-ATPase that exist with different isomers having different degrees of inhibition of the different isoforms.

Methods Using cyclobond chiral column we separated digoxin into two distinct chromatographic peaks each with different retention times. Optical rotation was +17° and +3° respectively for the two peaks but both isolates showed the same mass/change ratio of 780, identical to that of racemate digoxin. The effects of the isolates on cardiac contractility and AV conduction were evaluated in anesthetized guinea pigs (GP): 15 GPs were randomly given D, isolate 1 or 2. AV conduction was assessed by measuring PR interval and contractility by a Walton Brody strain gauge arch sutured to the left ventricular free wall. D or the isolates were infused continuously at 6 μg/kg/min.

Results D and isolate 1 caused a progressive increase in the PR interval while isolate 2 did not progressively increase PR. D and isolate 2 caused a progressive increase in contractility (% change from the baseline) while isolate 1 caused little change in contractility.

Conclusions We concluded that D can be chirally separated with one isolate causing progressive PR prolongation and the other contractile augmentation. (Figure)

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